We are carrying out studies of the histone modifications over the insulin gene locus and its neighborhood in human islet cells, in an attempt to identify long range regulatory influences that may affect insulin gene expression. We have identified an extended domain of open chromatin structure that includes not only the insulin gene, but also the upstream tyrosine hydroxylase gene and the downstream Igf2 and Igf2-AS genes. Unlike most loci, in which activating histone modifications are restricted to the neighborhood of gene promoters, these modifications are more or less uniformly distributed over the entire extended region. Transcripts, including from intergenic regions, can be detected throughout and are probably related to the distribution of histone modification marks. In other work, we are carrying out measurements of long range physical contacts within the nucleus between the insulin promoter and other genomic sites. We are now exploring these long-range interactions in order to determine whether they play a regulatory role coupling insulin expression to other genes important for insulin function. We have found that the insulin locus makes islet-specific contact with target genes that appear to be involved in the insulin secretory pathway.